tbuckley/cabot-search huggingface dataset:
IL believe: A phase 1/2, open-label, dose escalation and dose expansion study of TransCon IL-2 β/γ alone or in combination with pembrolizumab or standard-of-care chemotherapy in patients with locally advanced or metastatic solid tumors.
Authors: Alexander Starodub, Nashat Y. Gabrail, Ying Zhang, Davis Y Torrejon Castro, Sibel Slavsky, Stina Mui Singel, John D. Powderly
Journal: Journal of Clinical Oncology (2022)

TPS2695 Background: Advances in immunotherapy have led to significantly improved survival and quality of life in some cancer patients, but many with less immunogenic tumor types derive suboptimal clinical benefit. Recombinant human interleukin-2 (IL-2, aldesleukin) can induce a response rate of ̃15% in metastatic renal cell carcinoma and metastatic melanoma, yet toxicities (vascular leak syndrome, cytokine storm) have limited its use. TransCon IL-2 β/γ, a novel prodrug with sustained release of a receptor-selective IL-2 (IL-2 β/γ), was designed to optimally address drawbacks of aldesleukin: potent activation of undesired IL-2Rα + cell types and high C max with rapid clearance. TransCon IL-2 β/γ comprises 3 main components: IL-2 β/γ, a methoxy polyethylene glycol (mPEG) carrier molecule, and a linker connecting the two. Under physiological conditions, TransCon IL-2 β/γ releases active IL-2 β/γ from the mPEG carrier through cleavage of the TransCon Linker. This results in a lower C max and much longer effective t ½ of free IL-2 β/γ compared to aldesleukin. PD-1 expression at the cell surface of activated cytotoxic T cells and natural killer cells provides a clear rationale to study TransCon IL-2 β/γ alone or in combination with pembrolizumab. Methods: IL Believe is a multicenter, first-in-human, Phase 1/2 study in 3 parts in adult patients with locally advanced or metastatic solid tumors. All patients need ≥1 measurable lesion per RECIST 1.1 and an ECOG score of ≤ 2. The primary objectives are to evaluate safety and tolerability, and to define the maximum tolerated dose and recommended Phase 2 dose (RP2D) of TransCon IL-2 β/γ alone or in combination with pembrolizumab. Parts 1 and 2 Dose Escalation (Phase 1) use a standard 3+3 design with increasing doses of intravenous (IV) TransCon IL-2 b/g alone (Part 1) or with 200 mg IV pembrolizumab in solid tumors where pembrolizumab monotherapy may have clinical activity (Part 2). Each part will enroll ̃15 patients. Part 3, Combination Dose Expansion (Phase 2) will evaluate preliminary clinical efficacy of TransCon IL-2 β/γ at the RP2D determined in Part 2, combined with chemotherapy. Platinum Resistant Ovarian Cancer is currently planned for dose expansion with other indication specific cohorts to be included in a subsequent amendment. Each cohort will be analyzed using a Simon 2-stage design and will enroll ̃56 patients. Other key objectives include the evaluation of pharmacokinetics, pharmacodynamic biomarkers, and antitumor activity according to RECIST 1.1. Recruitment started in January 2022 and is ongoing (NCT05081609). Clinical trial information: NCT05081609.
Co-occurring mutations in the DDR pathway and tumor-associated genes for predicting immunotherapeutic efficacy in non-small cell lung cancer patients.
Authors: Louqian Zhang, Zhichao Fu
Journal: Journal of Clinical Oncology (2022)

e20539 Background: In recent years, the advent of immunotherapy had provided a new approach for non-small cell lung cancer (NSCLC) patients. However, only a small subset of patients can benefit from immune checkpoint inhibitors (ICIs) and the majority of patients still show poorly durable responses. Although some biomarker for predicting clinical efficacy of immunotherapy has been reported, the more proper predictive biomarker is required to screen dominant populations for ICI efficacy. Methods: A total of three publicly available datasets of NSCLC patients treated with immunotherapy were collected for analysis. The discovery contained 57 NSCLC patients sequenced by WES from Miao et al. and another cohort of 75 patients with clinical data and WES data download from Hellman et al. studies. We collected two MSK-IMPACT cohorts including 240 and 350 NSCLC immunotherapy patients used as validation set from cBioPortal(www.cbioportal.org). Results: We detected 79 mutation genes (mutation frequency &gt; 5% cases) associated with a better progressive free survival PFS (HR &lt; 1, P value &lt; 0.05) by univariate Cox regression analysis in the discovery cohort. The survival analysis results indicated that patients who carried co-occurring mutations of GRIN2A, FAT1, FLT1, ASXL2, PTPRS , and DDR pathway showed a longer PFS (p = 0.004, HR = 0.37, 95% Cl 0.235-0.644). Notably, comparing with the non-co-mutation group, the higher tumor mutation burden (TMB)(P &lt; 0.01) and more durable clinical benefit(P &lt; 0.05) have been detected in the co-mutations group. Next, we validated our findings using two independent validation cohorts who received ICI therapies from MSKCC, the results showed that PFS was significantly prolonged in the co-mutation group (p = 0.036, HR = 0.67, 95%CI 0.47-0.97), and with no significant difference in overall survival. Additionally, the TMB was significantly higher in the co-mutation group than that harbored non-co-mutation in two validation cohorts(p &lt; 0.01). Conclusions: In this study, we found that co-occurring mutations in five genes and DDR pathways can predict a better immunotherapy efficacy of NSCLC. Therefore, the co-mutation signature may have great potential as a biomarker for guiding immunotherapy of NSCLC.
Quality of end-of-life care for patients with multiple myeloma: A 12-year analysis of a population-based cohort.
Authors: Ghulam Rehman Mohyuddin, Aynharan Sinnarajah, Anastasia Gayowsky, Kelvin K. Chan, Hsien Seow, Hira Mian
Journal: Journal of Clinical Oncology (2022)

12031 Background: Despite treatment advances, multiple myeloma (MM) remains a significant source of morbidity and mortality. The end of life for patients with MM has not previously been examined within the context of a population-based cohort in a publicly funded health system. Methods: We retrospectively analyzed patients with death attributable to MM between 2006-2018 using ICES linked databases in the public health care system in Ontario, Canada. Aggressive care was defined as two or more emergency department visits in the last 30 days before death, at least two new hospitalizations within 30 days of death, or an ICU admission within 30 days of death. Supportive care was defined as physician house call 2 weeks before death, or a palliative nursing or personal support visit at home in last 30 days before death. Multivariable logistic regression models were used to assess for factors predisposing to aggressive or supportive care. Patients were stratified based on receipt of autologous stem cell transplant (ASCT). Results: In total, 5095 patients were included (Table). Overall, 23.2% of patients received chemotherapy in last two weeks of life and 55.6% of patients died in the hospital. Most patients were admitted to hospital within the last 30 days of life (73.4%:ASCT cohort, 61.4%:non-ASCT cohort). A minority received aggressive care at end of life (28.3%:ASCT cohort, 20.4%:non-ASCT cohort), and a majority received supportive care at end of life (65.4%:ASCT cohort, 61.5%:non-ASCT cohort). Multivariate regression models showed that patients ≥ 80 years (compared to 60-69) were less likely to receive aggressive care (OR=0.54, 95% CI=0.42-0.68), and those with residence in smaller size community of &lt; 10,000 were more likely to receive aggressive care (OR=1.89, 95% CI=1.5-2.4). Supportive care was significantly less likely to be received by patients (OR=0.72, 95% CI= 0.59 to 0.88) and more likely to be received by patients aged 18-49 (OR=1.9, 95% CI=1.2-3.1). Neighbourhoods with lowest income quintiles (OR=0.65, 95% CI=0.53-0.78) were less likely to receive supportive care. When trended over time, patients receiving supportive care at end of life increased (56.0% in 2006 to 70.3% in 2018). Conclusions: We demonstrate that despite improvements over time, a substantial number of patients with MM experience aggressive care and hospitalizations at the end of life. Despite this being a publicly funded system, disparities in end-of-life care based on age, income and area of residence are present.[Table: see text]
A phase I trial of elimusertib in combination with cisplatin or with cisplatin plus gemcitabine in advanced solid tumors with an emphasis on urothelial carcinoma.
Authors: Ryan Leibrandt, Paul Henry Frankel, Jan Hendrik Beumer, Naoko Takebe, Ming Yin, Hamid Emamekhoo, Primo "Lucky" N. Lara, Steven Gore, Mamta Parikh
Journal: Journal of Clinical Oncology (2022)

TPS3174 Background: Cisplatin, a well-established backbone of combination therapy of various advanced solid tumors, inhibits DNA synthesis by forming DNA cross-links and adducts. Despite the activity of cisplatin, tumor cells can either be refractory or develop resistance to treatment. Cisplatin has been demonstrated to cause cell cycle G2/M arrest, which may allow for DNA damage response (DDR) and repair. Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad 3-related (ATR) protein kinases are key regulators of DDR, and contribute to maintaining genomic integrity in response to various exogenous and endogenous genotoxic insults like cytotoxic chemotherapy. In fact, cisplatin has been shown to transiently increase ATR expression. Inhibitors of ATR have been studied in combination with cisplatin both in vitro and in vivo, demonstrating enhanced activity. The oral small molecule ATR inhibitor elimusertib, which has been studied as a single agent in a Phase I study, has also demonstrated enhanced activity with cisplatin in vitro in lung cancer and bladder cancer cell lines. We sought to conduct a Phase I study evaluating the combination of elimusertib with cisplatin or with cisplatin and gemcitabine. Methods: In the first cohort, patients with histologically confirmed advanced solid tumors for which cisplatin-based therapy would be considered appropriate, who exhibit adequate organ function, and have received &lt; 300 mg/m 2 of cisplatin previously are treated with cisplatin on Day (D) 1 and with elimusertib on D2 &amp; 9 of each 21-day cycle. The study follows a phase I queue (IQ) 3+3 dose escalation design, following standard practices for dose-limiting toxicity (DLT) impact on escalation, and when the maximum tolerated dose (MTD) is established with cisplatin alone, this will inform the first dose level of the next cohort, in which patients will be treated with cisplatin on D1, gemcitabine on D1 &amp; 8, and elimusertib on D2 &amp; 9 of each 21-day cycle. An expansion cohort will enroll urothelial carcinoma patients when the second MTD is established. The primary objective of the study is to evaluate the safety and MTD of elimusertib in combination with cisplatin, as well as in combination with cisplatin and gemcitabine. Secondary study objectives include evaluation of pharmacokinetics of elimusertib in these combinations, preliminary efficacy, and evaluating the association between ATM expression and responses to therapy. Currently, 6 patients have been enrolled to the first cohort of the study. Clinical trial information: NCT04491942.
Biallelic loss of TP53, PTEN, and RB1 in association to aggressive clinical features and poor outcomes in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Corinne Maurice-Dror, Nicolette Fonseca, Cameron Herberts, Edmond Michael Kwan, Catarina Kollmannsberger, Wilson Tu, Daniel Joseph Khalaf, Matti Annala, Elena Schönlau, Cecily Q. Bernales, Gráinne Donnellan, Joanna Vergidis, Krista Noonan, Daygen L. Finch, Muhammad Zulfiqar, Miller Stacy, Alexander William Wyatt, Kim N. Chi
Journal: Journal of Clinical Oncology (2022)

5055 Background: Deleterious alterations in tumor suppressor genes (TSGs) TP53, RB1, and PTEN are potential markers of small cell neuroendocrine prostate cancer (SCNP), and androgen receptor pathway inhibitor (ARPI) resistance. We examined the outcomes and clinical features of mCRPC patients (pts) harboring biallelic loss in 0, 1, 2 or all 3 TSGs. Methods: We identified 210 consecutive mCRPC pts providing ≥1 plasma cell-free DNA sample with ≥20% circulating tumor DNA fraction (ctDNA%) during their mCRPC disease course. ctDNA% ≥20% enabled sensitive characterization of biallelic TSG loss (including by homozygous deletions and mutation plus somatic loss-of-heterozygosity; LOH). Patient records were reviewed for baseline characteristics, SCNP histology, and presence of liver metastases. We investigated associations between TSG loss and the following clinical outcomes: PSA response (PSA decline ≥50% (PSA50 RR)), progression free survival (PFS) on 1L therapy, and overall survival (OS) from 1L therapy. Results: Median follow-up was 16.5 months (range: 0.4-112.4) and OS event rate was 95%. Median age at 1L mCRPC was 71 years (range: 48-98). Most pts were ECOG PS 0-1 (79%) and 13% had liver metastases. 91% received ARPI for 1L mCRPC and 7% received ARPI for castration-sensitive disease. TP53 was primarily inactivated by somatic mutation plus LOH (90%), whereas RB1 (71%) and PTEN (86%) were more commonly inactivated by homozygous deletions. Compared to pts without evidence of biallelic TSG loss, pts with loss of 3 TSGs were significantly enriched for de-novo M1 disease (86 vs. 60%, p=0.05) and liver metastases (28.5 vs. 6.8%, p&lt;0.05). Ten pts (4.7%) had histologically confirmed SCNP and provided ctDNA at time of SCNP diagnosis. Of these, 7 (70%) had biallelic loss of ≥2 TSGs. For all pts receiving 1L therapy, loss of ≥1 TSG(s) was associated with decreased OS (HR: 1.86, 95% CI: 1.40-2.48, p&lt;0.01) and PFS (HR:1.74, 95% CI 1.29-2.34, p&lt;0.01) compared to pts with no biallelic TSG loss. Furthermore, a cumulative increase in the number of TSGs lost was associated with an incremental reduction in OS and PFS (Table). Conclusions: In a cohort enriched for poor prognosis (i.e. high ctDNA%), cumulative loss of TSGs is associated with aggressive disease features and poor clinical outcomes. These patients may benefit from alternative treatment intensification strategies. [Table: see text]
Development of an electronic health record registry to facilitate collection of Commission on Cancer (CoC) metrics for patients undergoing surgery for breast cancer.
Authors: Heather G. Lyu, Olga Kantor, Alison Laws, James McDonald, Lisa Pham, Laura Stewart Dominici, Julie Vincuilla, Chandrajit P. Raut, Bryan Danilchuk, Lara Novak, Tonia Parker, Tari A. King, Elizabeth A. Mittendorf
Journal: Journal of Clinical Oncology (2022)

1549 Background: Accurate and efficient data collection is a challenge for quality improvement initiatives and clinical research. We describe the development of a custom electronic health record (EHR) based registry to automatically extract structured Commission on Cancer (CoC) axillary surgery specific metrics from a custom synoptic note template included in the operative reports for breast cancer patients undergoing surgery. Methods: The “Smart” functionality of our enterprise-based EHR system was leveraged to create a custom Smart phrase to capture axillary surgery specific variables. A multidisciplinary team developed structured data elements correlating to each axillary surgery-specific variable. These data elements were then included in a note template for the operative report. Each variable could be aggregated and converted into a single flat database through the EHR’s reporting workbench and serve as a live, prospective registry for all users within the EHR. Results: The final axillary surgery-specific note template in a synoptic format allowed for efficient and easy entry and automatic collection of breast cancer specific metrics. From initial adoption in February 2021 through December 2021, there were 1,254 patients who underwent breast surgery with axillary surgery. The operative notes allowed for automatic capture of metrics from 60.5% (n = 759) of patients. Data capture improved from 37.6% in the initial adoption period of six months to 86.2% in the last five months. Capture rate in December 2021 was 98%. Conclusions: We were able to demonstrate successful implementation of provider driven structured data entry into EHR systems that permits automatic data capture. The end result is a custom synoptic note template and a real-time, prospective registry of breast cancer-specific CoC metrics that are robust enough to use for quality improvement initiatives and clinical research.
Updated demographics at the only public oncology clinic in Belize.
Authors: Wayne Wong, James Dickerson, Rupali Sood, Yannis Valtis, Ramon Argenes Yacab, John Lattin, Philip Garrity, Ami Siddharth Bhatt, Franklin W. Huang
Journal: Journal of Clinical Oncology (2022)

e18787 Background: Belize is a middle-income Caribbean country without comprehensive cancer care capacity and poorly described cancer epidemiology. In 2020, we reported some of the first cancer demographics from the country. This was made possible by a capacity building partnership with the only public oncology clinic in the country at Karl Heusner Memorial Hospital (KHMH). Here we provide an update on demographic trends at this clinic. Methods: We performed a retrospective chart review of all available patient data at the KHMH clinic from December 2020 to December 2021. This was compared to data from the clinic’s founding in 2018 through its first 12 months. Results: From December 2020 through December 2021, the clinic saw 332 patients, an increase of 141% from the 236 patients seen over the first 12-month period of the clinic. In 2021, 250 (75%) patients had a confirmed pathologic diagnosis of cancer, with 78 (23%) remaining under clinical suspicion. This is in comparison to 63% of patients with a pathologic diagnosis in 2018. H&amp;E staining alone remained the only publicly available pathologic service. Patients were predominantly female (67%) with a median age of 54 (Range: 2-95). The most common histologies (n = 332) were breast (29%), cervical (11%), colorectal (8%), prostate (4%), gastric (4%), and lung (3%). Of patients with histologically confirmed cancer, 221 (66%) were able to be fully staged. Patients predominantly presented with later stage disease (25% Stage III, 34% Stage IV). At the end of 2021, out of all patients tracked longitudinally over the year (n = 332), 24% remained in need of full diagnostic assessment, 34% were on curative treatment (predominantly cytotoxic chemotherapy), 22% were under surveillance, and 18% were receiving palliative chemotherapy or best supportive care due to advanced disease. This is in comparison to 2018, when there was no capacity to administer chemotherapy at KHMH and patients were referred to either private clinics or out of the country. Conclusions: The burden of cancer in Belize is significant and diverse. Compared to 2018, in 2021, the number of patients seen at KHMH increased 141%, as did the percentage of patients with histologically confirmed cancer (120% increase). Chemotherapy treatment was made possible through procurement of a chemotherapeutic stock at KHMH due to key partnerships with the Belizean government, hospital administration, and crucially, the only medical oncologist in the nation. This has led to chemotherapy being available at a public clinic in the country for the first time. Despite this progress, patients continue to present at late stages and many cannot access cancer care due to limited resources, cost, and low public awareness. This further affirms the need for infrastructure investment and early detection programs to improve cancer outcomes in Belize.
Overall survival (OS) of patients with TRK fusion–positive cancer receiving larotrectinib versus standard of care (SoC): A matching-adjusted indirect comparison (MAIC) using real-world data (RWD).
Authors: Carsten Bokemeyer, Noman Paracha, Ulrik Niels Lassen, Antoine Italiano, Sean D Sullivan, Marisca Marian, Marc Mardoche Fellous, Jesús García-Foncillas
Journal: Journal of Clinical Oncology (2022)

6579 Background: Larotrectinib trials in Tropomyosin Receptor Kinase (TRK) fusion cancer population were single arm trials and therefore limited comparative effectiveness data with larotrectinib are available.MAIC is typically used to balance population characteristics to facilitate cross-study comparisons. The objective of this study was to use MAIC to compare efficacy of the highly specific TRK inhibitor larotrectinib vs. SoC. Methods: Individual patient data from larotrectinib trials (NCT02122913, NCT02637687, NCT02576431) were compared with published aggregate SoC data from patients with locally advanced/metastatic TRK fusion cancer identified in the Flatiron Health/Foundation Medicine clinico-genomic database (Demetri et al. Ann Oncol. 2021). Prior to matching, eligible patients were ≥18 years and had to have received ≤4 lines of prior therapy (LoPT). Patients were matched on available common baseline characteristics (Table). Overall survival was the only endpoint assessed and was defined as time from locally advanced/metastatic disease diagnosis to death. The analyses included: 1) a log-rank test of equality to test whether the two groups were similar before larotrectinib initiation; and 2) estimation of treatment effect of larotrectinib vs. SoC. Hazard ratios (HRs) were used to compare the 2 groups. MAIC assumes that all observed and unobserved prognostic factors are adjusted for in the analysis. Results: 85 larotrectinib patients and 28 SoC patients were included. After matching, log-rank testing suggested no difference between the 2 groups (P=0.26), and larotrectinib was associated with a 78% lower risk of death (adjusted HR: 0.22 [95% confidence interval: 0.09, 0.54]; P=0.001), compared to SoC. Conclusions: This analysis suggests longer overall survival with larotrectinib, compared to SoC, in adult patients with TRK fusion cancer. The current analysis was limited to the prognostic variables available in the RWD. Further data are warranted to confirm those results. [Table: see text]